BR112020020500A2 - PHARMACEUTICAL COMPOSITION, METHOD OF MANUFACTURING THE PHARMACEUTICAL COMPOSITION AND METHOD OF TREATING A CHRONIC WOUND WHICH INCLUDES, BUT NOT LIMITED TO, A LEG ULCER, DIABETIC FOOT ULCER OR ULCER ARISING FROM A INDIVIDUAL PRESSURE ULCER - Google Patents

Abstract

pharmaceutical composition, method of manufacturing the pharmaceutical composition and method of treating a chronic wound that includes, among others, a leg ulcer, diabetic foot ulcer or pressure ulcer in an individual. the invention relates to new pharmaceutical compositions comprising 2, 4, 4'-trichloro-2'-hydroxydiphenyleter (triclosan) and a thickener for use in the treatment of chronic wounds, in particular, in the treatment of chronic diabetic wounds, such as ulcers in foot.

Description

PHARMACEUTICAL COMPOSITION, METHOD OF MANUFACTURING THE PHARMACEUTICAL COMPOSITION AND METHOD OF TREATING A CHRONIC WOUND THAT INCLUDES, BUT NOT LIMITED TO, A LEG ULCER, ULCER DIABETIC FOOT OR ULCER ARISING FROM PRESSURE IN AN INDIVIDUAL

[001] This invention relates to a pharmaceutical composition comprising 2, 4, 4′-trichloro-2′- hydroxydiphenyleter (triclosan) and a thickener for use in the treatment of chronic wounds and, in particular, in the treatment of diabetic foot ulcers .

[002] The treatment of chronic wounds grade (EPUAP) 3 and 4, full-thickness skin defect that fails to heal within 3 months, is an important therapeutic challenge, which is being exacerbated by the increase in conditions such as diabetes, obesity and vascular disorders that prevent wound healing. Up to 70% of chronic wounds can be encouraged to heal within 3 months, but it is very difficult to judge at the beginning what the 'treatable' wounds will be; for those stubbornly non-healing wounds, there are currently few treatment options, if any, supported by research.

[003] Despite being clinically and molecularly different, all chronic wounds are generally assigned to one of the three main clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. There is still a lot to learn about the mechanisms involved in the healing or lack of healing of the chronic wound pathology. This could be due to the fact that animal models fail to mirror the clinical characteristics of chronic wounds and, therefore, their use as models still prevents the discovery and testing of appropriate treatment regimes.

[004] Most chronic wounds are considered poorly vascularized. Persistent inflammation is characteristic of most chronic wounds and is also infected. This leads to a large influx and retention of innate immune cells in chronic wounds that are likely to inhibit many repair processes. A consistent obstacle in the healing of many chronic wounds is the accumulation of necrotic debris at the edge of the wound. This is the reason why the clinical practice of debriding the wound to establish a 'new and fresh' wound is frequent, which can lead to new efficient epithelialization.

[005] The pathogenesis of ulcers is due to neuropathic impairment of musculoskeletal balance, as well as immunological impairment resulting from leukocyte dysfunction and peripheral vascular disease, complicating these wounds with infection. The standard of care includes discharge, attentive debridement, maintaining the moist environment of a wound and, when cellulite is present, systemic antibiotics. Diabetic foot ulcers are an infection, ulceration or destruction of deep tissues associated with neurological abnormalities and varying degrees of peripheral vascular diseases in the lower limbs (World Health Organization definition, 1995).

[006] Diabetic foot ulcers are common and are estimated to affect 15% of all diabetic individuals during their lifetime. Diabetic foot ulcers are the consequence of several factors, which include peripheral neuropathy, reduced blood supply (ischemia due to peripheral arterial disease and microvascular disease), high plantar pressures and represent a significant risk for morbidity, loss of limbs and mortality. Peripheral neuropathy has been shown to be the single most common cause of foot ulceration. Ulceration can be attributed to a triad of peripheral neuropathy, biomechanical deformity and minor overlapping trauma. In general, the lack of sensitivity resulting from neuropathy is responsible for the unrecognized repetitive trauma and burden, which leads to the rupture of the skin and soft tissues, creating an entry point for infection. The inflammatory environment contributes to diabetic microangiopathy and worsening of local ischemia. The other factors in ulceration are trauma, deformity, callus formation and edema. Current treatments for diabetic foot ulcers include: debridement (surgical, enzymatic and / or dressing changes) and antibiotics. Debridement removes devitalized tissue, which can be the source of endotoxins that inhibit the migration of fibroblasts and keratinocytes to the wound. In addition to systemic antibiotics and surgical intervention, wound care is an important component of the treatment of diabetic foot ulcers. Topical Antibiotics in the Treatment of Ulcers

[007] The lack of available data makes it difficult to assess the effectiveness of topical antimicrobials for diabetic foot ulcers. Few systemic agents improve the results for diabetic foot ulcers, but several topical substances accelerate healing, including compounds containing silver for venous ulcers and oxyquinoline in ointment for ulcers due to pressure stage 1 to 2. A systematic Cochrane review (O'Meara et al., Antibiotics and antiseptics for venous leg ulcers.

Cochrane Database of the 2014 Systematic Reviews, Edition 1. Art.

No: CD003557) of antibiotics and antiseptics for venous leg ulcers concluded that some evidence supports the use of iodine alkoxomer.

The authors also concluded that the current evidence does not support the routine use of honey and silver-based products and that more evidence is needed before reaching conclusions about the efficacy of povidone-iodine, peroxide-based preparations, ethacridine lactate, chloramphenicol, framicetin, mupirocin, ethacridine or chlorhexidine in the healing of venous ulceration in the leg.

A systematic review (Game et al., Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review.

Diabetes / Metabolism Research and Reviews 2016; 32 (1 Suppl): 154- 68) on the effectiveness of several interventions to enhance the healing of chronic diabetic foot ulcers found a single study that did not demonstrate the benefit of iodine alkoxomer in cavity wounds and a study suggesting that zinc oxide tape improved necrotic wounds more than a hydrocolloid.

Another Cochrane review (Bergin et al., Silver based wound dressings and topical agents for treating diabetic foot ulcers.

Cochrane Database of Systematic Reviews 2006, Edition 1. Art.

No: CD005082.) Of silver-based wound dressings and topical agents for the treatment of diabetic foot ulcers did not find controlled randomized clinical trials (RCTs) that reported results on healing rates or infection resolution.

Likewise, a Cochrane review (Vermeulen et al., Topical silver for treating infected wounds.

Cochrane Systematic Reviews Database 2007, Edition

1. Art.

No: CD005486) of dressings containing silver or topical agents for the treatment of infected or contaminated chronic wounds concluded that there was insufficient evidence, based on three randomized studies, to recommend these treatments.

A Cochrane systematic review (Jull et al., Honey as a topical treatment for wounds.

Cochrane Database of Systematic Reviews 2015, Edition 3. Art.

No: CD005083) on topical honey for the treatment of wounds concluded, based on data from 19 clinical studies, that honey can reduce the healing time for mild to moderate burns of superficial and partial thickness, but did not significantly accelerate the healing of leg ulcers.

The authors considered that there was insufficient evidence to guide clinical practice.

Finally, a recent systematic review of the effectiveness of interventions in the treatment of diabetic foot infections found six studies that investigated the use of topical agents, but the methods and results did not allow the authors to draw any definitive conclusions.

Between the two studies on topical antibiotics, one found that an antimicrobial peptide, pexiganan in cream, had similar efficacy to a systemic antibiotic (ofloxacin) in the treatment of mildly infected diabetic foot ulcers, while another study of adjuvant therapy with a collagen sponge with gentamicin (in connection with systemic antibiotic therapy) it was difficult to interpret due to methodological problems (Peters et al., Interventions in the management of infection in the foot in diabetes: a systematic review.

Diabetes / Metabolism Research and Reviews 2016; 32 (1 Suppl): 145-53).

[008] Topical antimicrobials most frequently used in wound care practice are chlorhexidine, iodine, products containing silver, mupirocin and fusidic acid. In the past, acetic acid, honey, hydrogen peroxide, sodium hypochlorite, potassium permanganate and proflavin have been used.

[009] The basic structure for the effective prevention and treatment of diabetic foot disease often appears to be lacking (National Diabetes Foot Care Audit Report 2014- 2016), without a unilateral and effective treatment method. Traditional treatments today offer intermittent results with many patients experiencing repeated ulcerations and, eventually, amputation.

[010] A disadvantage with the use of topical antibiotics is that few agents have proven effective in clinical studies. In addition, almost all topical antibiotics have minimal penetration into intact skin or soft tissue, which limits use to open wounds without cellulite or the spread of infection to deep soft tissue. Other disadvantages to using topical antibiotics include that systemic absorption of some agents can occur if used on large wounds; agents can induce local hypersensitivity or contact dermatitis reactions; some agents can interfere with normal wound healing processes; the treatment can produce changes in the normal skin flora, which leads to other problems; topical applications are difficult to measure precisely; frequent applications may be necessary; the agents can be difficult to apply or aesthetically unacceptable to some patients, and the stored agent can become contaminated.

[011] Topical antimicrobials have traditionally been formulated in one of two ways. First, ointments, which are more occlusive, often contain petrolatum and are best used for dry lesions. Second, creams, which are less occlusive, can be washed with water, are less difficult and are better for wet lesions. A major problem with topical therapies is that no official surveillance agency has standardized and approved specific tests to establish the effectiveness and safety of these agents. Topical antiseptics are generally avoided in open wounds as they interfere with wound healing due to cytotoxicity to healing cells.

[012] There is a great unmet need for an effective topical treatment for chronic wounds, in particular diabetic foot ulcers and other chronic non-healing ulcerated wounds resulting from illness or injury.

SUMMARY OF THE INVENTION

[013] It has been determined that the compositions, in accordance with the claims of the present invention, provide an extremely effective and novel clinical solution. Pharmaceutical compositions comprising 2,4,4′-trichloro-2′-hydroxydiphenyleter (triclosane) and a thickener at 0.5% to 8% by weight of the composition allow a viscosity between 70,000 and

150,000 centipoise, or cPs (between 20 and 40˚C).

[014] The specific solution of the invention, that is, the new combination of active and non-active components and their variation allows, among others, a high and prolonged concentration of the antimicrobial agent to be packaged and retained at the infection site, enabling improvement of effectiveness of the active ingredient without some common disadvantages of the prior art.

[015] Furthermore, the invention facilitates treatment in an outpatient condition and better adherence by the patient to a regimen also improves the effectiveness of treatment in general.

[016] In one embodiment, the composition is formulated for topical administration. In particular, in the composition it can be in the form of an emulsion, but it can be in any topical form, such as a cream or paste that is suitable for application, i.e., wound accommodation.

[017] These compositions are shown by the depositor for being particularly effective in the treatment of chronic wounds. In use, the continued presence of triclosan in the composition of the present invention prevents or reduces the broad-spectrum microbial growth and inflammatory processes that occur in the underlying wounds. When the active is formulated in the form described above of the present invention, it has characteristics that promote the ideal conditions for the healing of the chronic wound when it is suitable for packaging. In a preferred embodiment, the chronic wound is a human wound.

[018] The treatment of a chronic wound may include, among others, delay, reduction and / or improvement of a symptom of the chronic wound, such as edema, discharge, discoloration, pain, calluses, thickened skin around the wound and, in stages advanced, fever and chills.

[019] A chronic wound can be any non-healing wound that includes, but is not limited to, a leg ulcer, a diabetic foot ulcer, a pressure ulcer, a burn or other ulcerative wound resulting from injury or illness.

[020] The chronic wound or ulcer is caused, at least in part, by one or more of the following: peripheral neuropathy, ischemia due to peripheral arterial disease, microvascular disease, biomechanical abnormalities and minor overlapping trauma.

[021] In particular, the use of the present invention for the treatment of diabetic foot ulcers has been shown to be particularly effective by the depositor. In many cases, the diabetic foot ulcer has not responded to any previous treatment with systemic or topical antibiotics in creams and dressings. A diabetic foot ulcer can usually comprise one or more calluses.

[022] In addition, the use of the composition for the treatment of diabetic foot ulcers is especially advantageous due to the typical requirement of existing treatments to limit or restrict the concentration of active ingredient placed at the site of infection, as well as reducing the potential risks of toxicity and systemic absorption.

[023] Diabetic foot ulcer treatment includes delaying, reducing and / or ameliorating any symptoms of diabetic foot ulcer, including edema, discharge, discoloration, pain, calluses, skin thickening around the ulcer and, in advanced stages , fever and chills.

[024] The composition is for use in combination with any ulcer that may result from diabetes. The use of the composition can be administered at any time in combination with therapy for diabetes. For example, the composition can be administered before and / or during and / or after alternative therapy for diabetes.

[025] Viscosity is a measure of the resistance of a fluid to deformation under shear stress. It is commonly perceived as "thickness". Dynamic Viscosity can be measured using a viscometer and provides a unit of measurement in centipoises (cPs) or millipascal seconds (mPa · s). One method is to measure the voltage using a Brookfield Viscometer and a C-bar T axis at 10 RPM at room temperature. In some embodiments, the composition may have a viscosity range of 70,000 - 100,000 cps, or 80,000 - 120,000 cps or 100,000 - 130,000 cps or 120,000 -

150,000 cps.

[026] In another embodiment, the thickener may be Carbopol, polyacrylic acid, guar gum, carbomer, cetyl palmitate or other gelling agent.

[027] The composition may further comprise a neutralizing agent. The neutralizing agent can be selected from one or more of triethanolamine, sodium hydroxide or potassium hydroxide.

[028] The formulation can also comprise water.

[029] The composition may further comprise an emulsifier. The emulsifier can be selected from one or more stearate derivatives, for example, glyceryl monostearate.

[030] In another embodiment, 2,4,4′-trichloro-2′-hydroxydiphenyleter (triclosane) may be present at a concentration between 0.1 and 2.0% or 0.1 and 4.0% by weight formulation.

[031] In another embodiment, the composition may comprise a silicone-based water repellent and / or skin conditioning agent.

[032] In a further embodiment, the composition may comprise absorption-promoting adjuvants.

[033] In a further embodiment, the composition may comprise one or more of the following ingredients: a surfactant, a bulking agent, a tonicity adjusting agent, a stabilizer, a preservative and a buffer.

[034] In the productions, the composition also includes additional elements such as: vegetable oils (almonds, coconut, olive), hydrogenated castor oil, Melaleuca alternifolia leaf oil (tea tree), fruit oil from Olea europaea (Oliva) , hydrogenated vegetable oil, Euphorbia cerifera wax (Candelilla), glyceryl dibehenate, tribehenin, glyceryl behenate, l-lysine hydrochloride, squalane, tocopheryl acetate, phytosphingosine, ceramides, castor oil, stearic acid, glycerol stearate, cetyl palmitate, fluid silicone: dimethicone, Nipastat, jojoba oil, liquid paraffin, carbomer, triethanolamine, Aloe vera, monopropylene glycol, tea tree oil, ferulic acid, triclocarbon, chlorhexidine (gluconate or undecylenate), diclofenac (sodium ), hyaluronic acid, Centella asiatica oil, calendula extract, shea butter, manuka oil.

[035] The composition may comprise at least one hydrophilic phase component and at least one hydrophobic phase component; wherein both the hydrophobic phase component and the hydrophilic phase component form most of the composition portion by weight.

[036] In a non-limiting example, the composition may comprise the following ingredients in the indicated desirable ranges: Ingredient Range (% by weight) Castor oil 0.5-3.0 Stearic acid 0.5-8.0 Glycerol monostearate (GMS 0,1-3,0 SE) Cetyl palmitate 0,1-, 0 Silicone fluid 200/100 CS 0,1-10 dimethicone Additional preservative 0,0-0,5 Jojoba oil 0,1-0, 5 Liquid paraffin 0.1-0.5 2,4,4′-trichloro-2′- 0,3-10 hydroxydiphenyleter (Triclosane) Water 35-95 Carbopol 5% 0.5-8.0 Aloe vera 0.1 -2.0 Monopropylene glycol (MPG) 2.0-15 Triethanolamine 0.1-2.0

[037] According to some embodiments, the composition is formulated for topical administration.

[038] The term "topic" refers to the administration of the composition at, or immediately under, the point of application. As used herein, "topical application" refers to application on one or more surfaces, which include keratinous tissue, that is, "topical application". Topical application or “topical application” may involve direct application to the desired substrate area. The topical preparation and / or composition can be applied by pouring, dripping or rubbing in, or by any other appropriate means.

[039] In addition, the composition may be in the form of an emulsion, cream, ointment, lotion or balm.

[040] In some embodiments, the composition can be combined with additional agents, such as a therapeutically effective amount of an anti-inflammatory agent and / or an effective amount of an analgesic to further improve patient comfort.

[041] The composition can be combined with another pharmaceutical agent. In an additional embodiment, the composition is used in combination with oral, parenteral or topical medication.

[042] In some embodiments, the composition for use in the treatment according to the applications described above can be combined with the use of one or more additional treatments. These may include debridement treatment, systemic antibiotic treatment and / or post-curative treatment. Debridement can occur immediately before application or conditioning of the composition in the wound. Antibiotics can be administered concurrently with the treatment of the invention. Wound dressing can be an advantage after treatment, every time the wound is treated again.

[043] In preferred embodiments, the treatment comprises wrapping the wound to the composition, dressing or covering the wound and repeating this treatment at least once, preferably on a regular basis, such as daily or weekly. In some embodiments, especially where the composition contains a large amount of water, the treatment comprises wrapping the wound with the composition, placing a dressing or dressing on the wound and repeating this treatment at least two or three times in the period of 7 days. This is to ensure that the dressing is not soaked and remains a sterile practical barrier. However, such treatment does not require debridement of the wound, since excess water acts to clean the entire wound surface.

[044] The composition can be administered for 3, 4, 5, 6, 7, 8 weeks or more. Peak response is achieved within 8 weeks or more after starting treatment. The patient may be in remission of symptoms for 4 to 12, 6 to 12, 6 to 18 weeks or more, including 16 to 36 months after treatment.

[045] The actual amount administered, and the rate and temple of the administration cycle, will depend on the nature and severity of what is being treated. The prescription of treatment, for example, decisions about dosage, etc., is ultimately the responsibility and discretion of general practitioners and other doctors, and usually takes into account the disorder to be treated, the patient's condition , the place of supply, the method of administration and other factors known to doctors. The composition can be administered once, twice, three or four times a day or periodically.

[046] The precise dose of the composition will depend on several factors, including the severity of the ulcer. The composition is preferably administered to an individual in a "therapeutically effective amount", this being effective to show the benefit to the individual.

[047] The invention further relates to a method of manufacturing a pharmaceutical composition, according to any preceding claim, wherein the method comprises the steps of: i) preparing an oil phase comprising triclosan; ii) preparing an aqueous phase comprising at least the thickener; and iii) mixing the oil phase and the aqueous phase together.

[048] In some embodiments, after mixing the phases, water can be added to adjust the final viscosity of the composition.

[049] The preparation of the aqueous phase may include the addition of one or more of the components selected from monopropylene glycol, triethanolamine, water, Aloe vera and / or a combination of these.

[050] The preparation of the oil phase can include one or more components selected from: castor oil, stearic acid, glycerol stearate, cetyl palmitate, fluid silicone, jojoba oil, liquid paraffin and / or a combination of these.

[051] The invention also extends to a method of treating a chronic wound that includes, among others, a leg ulcer, diabetic foot ulcer or pressure ulcer on an individual, comprising the administration of a composition as previously defined above. The composition can be administered as a topical formulation that fills the wound, optionally the wound can be covered with a dressing. In a preferred method, the composition is administered before and / or during and / or after debridement and / or systemic antibiotic treatment.

[052] The term "therapeutically effective amount", as used herein in the context of treating diabetic foot ulcers, means an amount capable of reducing the individual's ulcer size before the composition of the invention is administered.

[053] Treatment may include curative, mitigating or prophylactic effects. The term ‘treatment’ is used here to refer to any regimen that can benefit humans.

[054] More specifically, treatment includes "therapeutic" and "prophylactic" and these types of treatment should be considered in their broader context. The term "therapeutic" does not necessarily imply that an individual is treated until full recovery. Likewise, "prophylactic" does not necessarily mean that the individual will eventually not contract a disease condition.

[055] Consequently, therapeutic and prophylactic treatment includes improving the symptoms of a particular condition or prevention, or otherwise reducing the risk of developing a particular condition. The term "prophylactic" can be thought of as a reduction in severity or the onset of a particular condition. "Prophylactic" also includes preventing recurrence of a particular condition in a patient previously diagnosed with the condition. "Therapeutic" can also include the severity of an existing condition.

[056] The preferred characteristics for the invention are, like the other aspects, with the necessary modifications.

[057] The invention will now be further described by reference to the Figures, Examples and Treatments of Patients below.

[058] These are provided for the purpose of illustration only and should not be construed as limiting the invention. Figures

[059] Figure 1 (a) is an image of a diabetic foot ulcer in patient 1. The first ulcer is found on the dorsal interphalangeal joint on the second toe, with a size of 5p, 1 cm2;

[060] Figure 1 (b) is an additional image of patient 1 and the second diabetic foot ulcer is at the apex of the 1st toe, before debridement;

[061] Figure 2 (a) is an additional image, after debridement;

[062] Figure 2 (b) is an additional image after 3 to 4 weeks;

[063] Figure 3 (a) is an additional image after 4 to 6 weeks;

[064] Figure 3 (b) is an additional image at 6 weeks;

[065] Figure 4 (a) is an additional image at 8 to 9 weeks;

[066] Figure 4 (b) is an additional image just before it is fully healed;

[067] Figure 5 (a) (b) is an additional image of the healed apex of the 1st toe;

[068] Figure 6a is an image of a diabetic foot ulcer from patient 2, the image shows the ulcer before (on the left) and after (on the right) the debridement and cleaning;

[069] Figure 6b is an additional image of patient 2's diabetic foot ulcer, taken at 4/5 week intervals from the date of the first treatment; and

[070] Figure 7 is an additional image of patient 2, when the ulcer is fully healed. Examples

[071] The formulations shown below were prepared as follows:

1. Castor oil, stearic acid, glycerol stearate, cetyl palmitate, fluid silicone, jojoba oil and liquid paraffin were dissolved together.

2. Mixed well and heated to 60 ° C.

3. In a separate container, monopropylene glycol, triethanolamine, 50% water and carbomer of pH 5.5 were mixed together, using a Silverson high shear mixer at 20,000 rpm with fine mesh head.

4. The mixture was heated to 65 ° C

5. The active component (triclosan) was added to the mixture from step (1) just before stage (6) and mixed.

6. The oil phase mixture from step (1) was added to the water phase from step (3) and mixed well under high shear conditions using a Silverson high shear mixer.

7. When fully mixed, the Aloe vera solution was added and stirred.

8. The remaining cold water was added and stirred. The final pH was 5.5

9. The mixture was left to stand overnight to cool, then mixed again into the total batch. The mixture was poured / filled while still hot at approximately 40oC.

[072] Examples of% by weight range of component in the composition: Ingredient Range (% by weight) Castor oil 0.5-3.0 Stearic acid 0.5-8.0 Glycerol monostearate (GMS 0.1- 3.0 SE) Cetyl palmitate 0.1-2.0 Silicone fluid 200/100 CS 0.1-10 dimethicone Additional preservative 0.0-0.5 Jojoba oil 0.1-0.5 Liquid paraffin 0, 1-0.5 Triclosan 0.3-10 Water 35-95 5% Carbopol 0.5-8.0 Aloe vera 0.1-2.0 Monopropylene glycol (MPG) 2.0-15 Triethanolamine 0.1- 2.0

[073] By varying the proportion of thickener from 0.5% to 8% of the weight of the composition, according to the examples below, the viscosity of the resulting product was between 70,000-150,000 cPs. The paste was typically thickened using Carbopol Triethanolamine, however, polyacrylic acids, guar gum or xanthan gum could be used as a thickener or other standard cosmetic or pharmaceutical thickeners suitable for topical use.

[074] Several different examples of compositions were then produced with the following% by weight: EXAMPLE 1 Materials% in Phase weight Castor oil 2.00 Stearic acid 6.00 GMS SE 2.00 Cetyl palmitate 1.00 Fluid silicone 1, 00 Preservative 0.20 A additional Jojoba oil 0.10 Liquid paraffin 0.10 MPG 10.00 Triethanolamine 1.55 Hot water at 65 ° C 39.65 B Carbopol 5.00 Triclosan 0.50 C Aloe vera 0.50 Fragrance 0.15 D Cold water 30.25 E

[075] The ingredients of phase A were dissolved at a temperature of 60 ° C. Phase B ingredients were mixed using a Silverson high shear mixer. Phase C was added to phase A and stirred until dissolved. Phase B was then added to phase A. Phase D was then added and mixed using a Silverson high shear mixer. Phase E was also added during mixing. EXAMPLE 2: Materials% in Phase weight Castor oil 2.0 Stearic acid 1.5 GMS SE 0.5 Cetyl palmitate 0.5 Fluid silicone 1.0 Preservative 0.2 A additional Jojoba oil 0.1 Liquid paraffin 0 , 1 Triclosan 1.0 B Hot water at 60 ° C 80.4 C Carbopol (5%) 2.0 Aloe vera 10.1 0.5 MPG 10.0 Triethanolamine 0.2 D

[076] The ingredients of phase A were dissolved together at a temperature of 70 ° C until the phase was clear. Phase C ingredients were mixed together using a Silverson high shear mixer. Phase B was added to phase A and stirred until dissolved. Phase C was then added to phase A. Phase D was then added and mixed using a Silverson high shear mixer. EXAMPLE 3 Materials% in Phase weight Castor oil 2.0 Stearic acid 1.5 GMS SE 0.5 Cetyl palmitate0.5 Fluid silicone 1.0 Preservative 0.2 A additional Jojoba oil 0.1 Liquid paraffin 0.1 Triclosan 2.0 B MPG 10.0 Hot water at 60 ° C 79.4 Carbopol 2.0 C Aloe vera 0.5 Triethanolamine 0.2 D

[077] The phase A ingredients were dissolved together at 65 ° C until they were clear. Phase C ingredients were mixed together using a Silverson high shear mixer. Phase B was added to phase A and stirred until dissolved. Phase C was then added to phase A. Phase D was then added and mixed using a Silverson high shear mixer. EXAMPLE 4

Materials% in Phase weight Castor oil 2.0 Stearic acid 1.5 GMS SE 0.5 0.5 cetyl palmitate Fluid silicone 1.0 A Preservative 0.2 Additional Jojoba oil 0.1 Liquid paraffin 0.1 Triclosan 2.0 B MPG 10.0 C Hot water at 78.6 60 ° C Carbopol 5% 2.0 Aloe vera 10: 1 0.5 Triethanolamine 1.0 D

[078] The ingredients of phase A (oily) were dissolved together at a temperature of 65 to 80 ° C until they were clear. The phase C (aqueous) ingredients were mixed together using a Silverson high shear mixer. Phase B was added to phase A (oily) and stirred until dissolved. Phase C (aqueous) was then added to phase A (oily). Phase D was then added and mixed using a Silverson high shear mixer. EXAMPLE 5 Materials% by weight Phase

Castor oil 2 A Stearic acid 1.5 GMS SE 0.5 Cetyl palmitate 0.5 Silicone Fluid 200 100CS 1 Jojoba oil 0.1 Heavy liquid paraffin 0.1 Nipastat (optional preservative) 0 - 0.2 Triclosan 2 B Hot water (60 ° C) 32 C Carbopol 980 to 5% Sol 2 Monopropylene Glycol 10 Triethanolamine 1 Aloe Vera 10: 1 0.5 Cold water 46.6 D

[079] Example 5 was prepared as outlined in example 4.

EXAMPLES OF CLINICAL USES

[080] A cream formulation of triclosan, in accordance with an embodiment of the invention (Example 5), was applied to several patients, with conditions and symptoms presented as follows, as described below: Patient Profile 1:

[081] Female, 40 years old, diabetic. Neuroischemic. Heart rate: mono and biphasic pulse, depending on the climate. Indication of reduced arterial blood flow due to a blockage or low elasticity. Ex-smoker. Non-healing stage 3 diabetic dorsal foot ulcer.

[082] The patient had 2 ulcers: 1) one on the dorsal interphalangeal joint on the 2nd toe, the size of a 5 cent coin, 1 cm2; and 2) one at the apex of the 1st toe, the size of a 5 cent coin, 1 cm2. No evidence of osteomyelitis in the patient. Previous Treatment:

[083] The antibiotic Flucloxacillin was prescribed for 6 months intermittently and continuously, this treatment was discontinued for two weeks in the treatment with cream triclosan. After 6 treatment cycles, the patient was unable to clear the wound infection.

[084] The patient was also treated with products based on silver and iodine and separately with honey, but there was no healing.

[085] The toe looked like a sausage. With its concomitant morbidities and weight, amputation of the finger would not be advised, as it could not survive the surgery.

[086] Treatment with Triclosan in cream:

[087] The patient was treated twice a week. The ulcer was filled with the cream to the margin, so that the cream was level with the skin surface. The cream was not washed between treatments, but the ulcer showed a rigid debridement at the base of the ulcer before each treatment. Triclosan in cream was applied for 8 weeks. The cream was wrapped in the wound and a non-adhesive foam adhesive was applied. The patient then used rocker bottom soles to reduce weight and pressure. The treatment for this toe ulcer started on 11/3/17 and healed on 1/20/18. He did not take any other medication. Results:

[088] Both ulcers healed completely. Figures 1 to 5 further demonstrate that the cream triclosan of the invention is effective in the treatment of diabetic foot ulcers. Patient Profile 2:

[089] The male patient had 1 ulcer on the sole of his foot, the size of approximately a 50 cent coin.

[090] No evidence of osteomyelitis in the patient. Previous Treatment:

[091] After the antibiotic treatment cycle Flucloxacillin, the patient was unable to clear the wound infection. The patient was also treated with silver and iodine-based products and separately with honey, but healing did not occur. Chemotherapy treatment. Debridement performed on the ulcer and cleaning. Treatment with Triclosan in cream:

[092] Although the patient was receiving chemotherapy, triclosan cream was applied for 8 weeks. The cream triclosan was applied on alternate days, with a marked debridement and cleaning with sterile saline solution before applying the cream. In the last two weeks of treatment, the cream was applied daily. The cream was conditioned on the ulcer in order to be level with the skin surface and a non-adhesive dressing was applied. The patient then used rocker bottom soles to reduce weight and pressure. Results:

[093] Ulcer fully healed.

[094] Figures 6 and 7 demonstrate that the cream triclosan of the invention is effective in the treatment of diabetic foot ulcers. Patient Profile 3:

[095] A 65-year-old female with Raynaud's disease. The patient had very insufficient circulation with a single-phase pulse in her feet. The patient was suffering from severe chilblains that had begun to break and ulcerate, forming a chronic wound. Previous Treatment:

[096] No other treatment was helping to heal ulcerations. Treatment with Triclosan in cream:

[097] The cream was applied to the wound and covered with a Biatain dressing and then refitted and replaced the dressing once a week. After one month, the skin had healed and it took an additional 2 weeks to resolve the chilblains. Patient Profile 4:

[098] 92-year-old female patient, with ischemic limbs, wound trauma to the upper part of her foot. The wound was filled with fluid and was not healing. Previous Treatment:

[099] Wound care nurses used a standard treatment (dressing) to treat it for more than 2 months without improvement. Treatment with Triclosan in cream:

[100] The cream (wrapped in the wound) was applied and the Biatain dressing was put on, and then it was reconditioned and replaced with the dressing once a week. The wound healed in 3 weeks. Patient Profile 5:

[101] 50-year-old female patient with a 5-year history of nephrectomy. Warts on the bottom of the foot. The patient tried to treat herself with Bazooka (treatment for warts) in gel and nitrous oxide gas. She then came to the doctors with cellulite and a non-healing hole in her foot. Previous Treatment:

[102] Iodflex was used for a week, but the patient became very ill with the infection and was about to need intravenous antibiotics. Treatment with Triclosan in cream:

[103] The cream was packaged in the hole, a Biatain dressing was placed and then repackaged and replaced the dressing once a week. The patient felt better within a few days and the wound healed after 3 to 4 weeks of treatment, removing the need for intravenous antibiotics advantageously.

Claims (15)

1. PHARMACEUTICAL COMPOSITION, characterized by comprising: 2,4,4′-trichloro-2′-hydroxydiphenyleter (triclosan); and at least one thickener at 0.5% to 8% by weight of the composition, where the composition has a viscosity between 70,000 and 150,000 centipoise (cPs), between 20 and 40 ° C. 2. COMPOSITION, according to claim 1, characterized in that it is formulated for topical administration. COMPOSITION according to any one of claims 1 and 2, characterized in that the composition is in the form of an emulsion, cream, ointment, lotion or balm. 4. COMPOSITION, according to any one of the preceding claims, characterized in that the thickener is selected from one or more of Carbopol, polyacrylic acids, guar gum, carbomer, cetyl palmitate and / or other gelling agent. COMPOSITION according to any one of the preceding claims, characterized in that 2,4,4′-trichloro-2′-hydroxydiphenyleter is present at 0.1% to 4.0% by weight of the composition, more preferably at 0, 1% to 2.0% by weight of the composition. 6. COMPOSITION according to any one of the preceding claims, the composition being characterized by further comprising a therapeutically effective amount of an anti-inflammatory agent and / or an effective amount of an analgesic. 7. COMPOSITION according to any one of the preceding claims, the composition being characterized by comprising at least one hydrophilic component and at least one hydrophobic component, wherein the hydrophobic component or the hydrophilic component forms the largest portion of the composition by weight. 8. COMPOSITION, according to any one of the preceding claims, characterized for being for use in the treatment of a chronic wound. 9. COMPOSITION FOR USE, according to claim 8, characterized in that the chronic wound is selected from a non-healing wound that includes, among others, a leg ulcer, a diabetic foot ulcer, a pressure ulcer, a burn or other ulcerative wound resulting from injury or illness. 10. COMPOSITION FOR USE, according to any of claims 8 and 9, characterized in that the chronic wound or ulcer is caused, at least in part, by one or more of the following: peripheral neuropathy, ischemia due to peripheral arterial disease, microvascular disease , biomechanical abnormalities and minor overlapping trauma. 11. COMPOSITION FOR USE, according to any one of claims 8 to 10, characterized by being combined with the use of one or more treatments selected from a debridement treatment, a systemic antibiotic treatment and / or a post-curative treatment . 12. COMPOSITION FOR USE, according to any one of claims 8 to 11, the treatment being characterized by comprising wound dressing with the composition, dressing or covering the wound and repetition of the treatment at least once, preferably on a regular basis. 13. METHOD OF MANUFACTURING THE PHARMACEUTICAL COMPOSITION, as defined in any of the preceding claims, the method being characterized by comprising the steps of: i) preparation of an oil phase comprising at least triclosan and optionally one or more components selected from : castor oil, stearic acid, glycerol stearate, cetyl palmitate, silicone fluid, jojoba oil, liquid paraffin or a combination thereof; ii) preparation of an aqueous phase comprising at least the thickener and optionally one or more components selected from monopropylene glycol, triethanolamine, water and Aloe vera; iii) mixing the oil phase and the aqueous phase together; and iv) optionally, adding more water to adjust the final composition viscosity. 14. METHOD OF TREATING A CHRONIC WOUND THAT INCLUDES, BUT NOT LIMITED TO, A LEG ULCER, DIABETIC FOOT ULCER OR PRESSURE ULCER IN AN INDIVIDUAL, characterized by understanding the administration of the composition, as defined in any of claims 1 to 7, to the individual. 15. METHOD OF TREATMENT, according to claim 14, characterized in that the composition is administered as a topical formulation that fills the wound and optionally in which the wound is covered with a dressing.